No biomarker other than HER2 expression for anti-HER2 therapy has been established in gastric cancer. We explored serum ERBB-related biomarkers for efficacy in a phase II trial (WJOG7212G) of triweekly trastuzumab (Tmab) (first dose 8 mg/kg then 6mg/kg) in combination with 5-weekly S-1 (40-60mg, twice daily, for 21 days) plus cisplatin (60mg/m2, on day 8) for HER2-positive (IHC3 + , or IHC2+ and FISH+) advanced gastric or esophagogastric junction cancer.
Serum samples were collected in 31 of 44 patients enrolled in the phase II study. Serum HER2, EGF, TGF-alpha, neuregulin 1 (NRG1), HGF, IGF1 and TIMP1 were measured by ELISA at following 4 points; pre-treatment, immediately before 2nd and 4th Tmab administration, and after PD. Pre-treatment serum levels were compared between responders (CR + PR) and non-responders (SD + PD). Progression free survival (PFS) and overall survival (OS) were compared between the high and low groups divided at median of pre-treatment value of each serum marker.
Patient characteristics were: median age 65.0 years, males 23 (74%), PS 0-1 29 (93%), primary site of stomach 27 (87%), histology of diffuse type 14 (45%), IHC 3+ 22 (71%) patients. The response rate was 68% (95% CI 50 - 81). The median PFS was 183 days (95% CI 133 - 420). The median OS was 515 days (95% CI 373 - not reached). Pre-treatment HER2 and NRG1 levels were higher in responders than in non-responders (Mean; HER2 96 ± 68 ng/ml vs. 12 ± 2 ng/ml, p = 0.026, NRG1 2467 ± 886 pg/ml vs. 186 ± 186 pg/ml, p = 0.012). HER2, NRG1 and EGF levels decreased after treatment (p
Serum NRG1 may be a candidate of a predictive marker for the efficacy of Tmab in combination with S-1 plus cisplatin in patients with HER2 positive gastric or esophagogastric junction cancer.
Clinical trial identification
Protocol number: UMIN000008389; Release date: 9, July, 2012
Legal entity responsible for the study
West Japan Oncology Group
Taiho Pharmaceutical Co.,Ltd.
Y. Miura: Honoraria: Kyowa Hakko Kirin, Novartis. T. Takano: Honoraria: Chugai, Taiho. K. Yamazaki: Honoraria: Chugai, Taiho. S. Hironaka: Honoraria: Taiho. N. Boku: Honoraria: Taiho, Chugai, Bristol-Myers. I. Hyodo: Honoraria: Daiichi-Sankyo, Chugai, Taiho, Yakult Pharmaceutical Companies. All other authors have declared no conflicts of interest.